Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy

Robert M. Samstein, Chirag Krishna, Xiaoxiao Ma, Xin Pei, Ken Wing Lee, Vladimir Makarov, Fengshen Kuo, Jonathan Chung, Raghvendra M. Srivastava, Tanaya A. Purohit, Douglas R. Hoen, Rajarsi Mandal, Jeremy Setton, Wei Wu, Rachna Shah, Besnik Qeriqi, Qing Chang, Sviatoslav Kendall, Lior Braunstein, Britta WeigeltPedro Blecua Carrillo Albornoz, Luc G.T. Morris, Diana L. Mandelker, Jorge S. Reis-Filho, Elisa de Stanchina, Simon N. Powell, Timothy A. Chan, Nadeem Riaz

Research output: Contribution to journalArticlepeer-review

Abstract

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T-cell, natural killer, macrophage and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2 deficiency on ICB outcome and have important implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

Original languageEnglish (US)
Pages (from-to)1188-1203
Number of pages16
JournalNature Cancer
Volume1
Issue number12
DOIs
StatePublished - Dec 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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